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Smooth muscle cells (SMCs) play a role in medial vascular calcification, which can be stimulated by high levels of serum phosphate and inflammatory mediators. The aim of this study was to investigate whether mitogen-activated protein kinases (MAPKs) (p38 MAPK, ERK1/2, and JNK) and protein kinase A (PKA) can participate in inorganic phosphate (Pi)- and inflammation response-stimulated SMC calcification.We examined the change of Pi- and/or inflammation-stimulated human aortic smooth muscle cell (HASMC) calcification in the presence and absence of inhibitors or small interfering RNAs.Ca levels were increased in HASMCs incubated with 1.5–3.9 mM Pi, but not with 0.9 mM Pi or compared with non-Pi-treated HASMCs. Furthermore, the addition of interferon-γ (IFN-γ) increased pro-inflammatory cytokines [interleukin (IL)-1α, IL-6, and tumor necrosis factor-α (TNF-α)] in media containing Raw 264.7 cells. Ca levels were significantly increased in HASMCs cultured in IFN-γ-treated medium, compared with non-IFN-γ-treated medium in the presence of Pi (0.9–2.4 mM). The inhibition of p38 MAPK and PKA decreased HASMC calcification stimulated by Pi and IFN-γ-treated medium, though PKA inhibition produced a more significant reduction in calcification than p38 MAPK inhibition.These results indicate that PKA inhibition can efficiently reduce Pi- and inflammation-stimulated SMC calcification.